Background and Rationale: Pancreatic ductal adenocarcinoma (PDAC), which is the fourth leading cause of cancer deaths in the United States, carries an extremely dismal prognosis. There are currently no effective or even palliative therapies for PDAC, and present approaches have not reduced tumor pathogenesis or improved patient survival. They exhibit profound resistance to many chemotherapeutic treatments and the current standard-of-care therapies, such as Gemcitabine (Gem). Therefore, new insights into the etiology of PDAC progression along with its precise mechanisms of drug resistance need to be discovered. Cyr61 (Cysteine rich 61), a heparin-binding, cysteine-rich, secreted protein encoded by a growth factor-inducible gene, is frequently elevated in pancreatic cancer cells and in precursor lesions. Our preliminary studies found that Cyr61 plays a positive role in pancreatic carcinogenesis and drug resistance. It regulates the expression of Sonic Hedgehog (SHh), which is widely linked to the maintenance, progression and Gem resistance of PDAC. However, the mechanism(s) by which Cyr61 exerts its overwhelming actions remains elusive. Hypothesis: Guided by the results of our preliminary studies, we hypothesize that Cyr61 is a key upstream positive regulator of SHh signaling, and it is through the SHh signaling that Cyr61 modulates pancreatic cancer growth and progression. The data lead us to further hypothesize that blocking Cyr61 signaling in a chemo- resistant setting is more effective than inhibiting the pathways in the first line treatment. Specific Aims: The specific aims of this application are to: (1) determine the molecular mechanisms through which Cyr61 regulates SHh expression and its down-stream mediators in pancreatic cancer cells, (2) elucidate the mechanisms whereby Cyr61 regulates the tumor growth and invasive phenotypes of pancreatic cancer cells and (3) explore the role of Cyr61 in enhancing chemoresistance of PDAC cells using both in vitro and orthotopic xenograft tumor models. The involvement of SHh will be investigated. Significance: Completion of these three aims will provide a mechanistic characterization of Cyr61 as a novel molecular target for pancreatic cancer therapy. Therefore, the proposed studies have the potential to impact the clinical treatment of pancreatic cancer patients. PUBLIC HEALTH RELEVANCE: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths in the United States. A patient with PDAC has the worst survival rate of any solid tumor due to its late detection, early metastasis, and resistance to conventional chemotherapy. We have suggested that Cyr61 may be an early and late mediator of PDAC. This insight is developed from our recent findings which indicate that Cyr61 regulates Sonic Hedgehog (SHh) expression. Cyr61 promotes multiple crucial events associated with the progression of the disease and resistance to chemotherapy. The objectives of this project are to evaluate the mechanism whereby Cyr61 regulates SHh expression in pancreatic cancer, as well as uncover the mechanisms by which Cyr61 promotes tumor progression and metastatic growth to the distant organs. The role of Cyr61 in resistance to chemotherapy will also be evaluated. We are anticipating that the outcome of these studies will propose that targeting Cyr61 can provide a new treatment option for patients with pancreatic cancer.